Cocaine is a powerful rewarding and euphoric drug of abuse which has become a major public health threat for several reasons. The drug is highly addictive and toxic, and the risk for HIV infection increases among intravenous poly-drug users through needle sharing and the immunosuppressive effects of both cocaine and opiates. In addition, simultaneous use of cocaine and alcohol is one of the most prevalent two-way drug combination for substance abuse-related death, as perceive by the Drug Abuse Warning Network. Recent studies have detected cocaethylene in postmortem blood, liver and neurological tissues as a metabolic product of concurrent cocaine and alcohol use. Since the combination of cocaine and alcohol is associated with enhanced and prolonged euphoria, we hypothesize that one possibility is the! formation of a neuroactive metabolite which may be responsible for the magnified reinforcing effects of cocaine and alcohol abuse. Neurochemical studies have suggested that blockade of the dopamine (DA) transporter is the primary mechanism responsible for the reinforcing properties of cocaine-related drugs, leaving more DA available within the synapse for post-synaptic activity. Although it is postulated that cocaethylene is a more powerful reinforcing and euphoric drug than cocaine, the drug is equipotent to cocaine as an inhibitor of the DA transporter. Therefore, we presume that additional neurotransmitter systems may be associated with the rewarding properties of these drugs. That the opioid system may be involved in the euphoric effects induced by cocaine is supported by several studies indicating elevated levels of endogenous opioid peptides with concomitant regulation of opioid receptors following exposure to cocaine. In addition, cocaine self-administration is suppressed in rhesus monkeys treated with the mixed agonist/antagonist opiate, buprenorphine. The development of new therapeutics to treat cocaine abuse is a fundamental issue, since several drugs which affect the dopaminergic and serotoninergic systems have generally failed to suppress cocaine craving. In view of the current state, we reasoned that a definitive investigation of the neurochemical effects of cocaine and cocaethylene on opioid neurotransmitters and receptors may establish the role of the opioid system in the euphoric and rewarding effects of these drugs. To establish the validity of this hypothesis, we propose to investigate alterations in the level of opioid peptides following acute and chronic exposure to cocaine and cocaethylene and to determine changes in opioid receptor binding following exposure to the drugs. Studies will also be focused to determine a possible correlation between alterations in monoamine levels and opioid peptide concentrations in critical brain regions following prolonged exposure to cocaine and cocaethylene. We anticipate that these studies will further establish the neurochemical effects of cocaine and also may elucidate the mechanism(s) underlying cocaethylene's magnified euphoric effects. Moreover, results of this project may provide a new approach for the development of therapeutics to treat cocaine abuse.